The 1,25α-dihydroxyvitamin D3 (1,25D) is the most active metabolite of vitamin D. It performs its biological actions by binding specifically to its nuclear receptor, the vitamin D receptor (VDR). The endocrine system of vitamin D plays a critical role in regulating the phosphorus and calcium metabolism, by stimulating intestinal absorption of these essential minerals and their mobilisation in bone tissue. Thus, vitamin D deficiency or resistance to its actions produces clinical signs at bone level, such as rickets in children or osteomalacia in adults.
Although the actions on the phosphorous and calcium metabolism are the best known, epidemiological, biochemical, cellular, or molecular genetic studies have shown their involvement in other physiological processes, since they inhibit the proliferation and induce the cell differentiation, and pathologic processes, such as psoriasis, diabetes, osteoporosis, and autoimmune, degenerative, endocrine, cardiovascular, infectious, or neoplastic diseases (De Luca H. Historical overview of vitamin D. In Vitamin D, 3rd Ed, Feldman D, Pike J W, Adams J S (Eds). Academic Press, London, U K, 2011, Volume 1, pp 3-12).
In cancer, treatment with vitamin D blocks the cell cycle and induces apoptosis, thus inhibiting tumour growth and contributing to tumour suppression. Numerous studies have evaluated the use of vitamin D as an anti-neoplastic agent, alone or in combination with other drugs for treating cancer. Vitamin D has been combined with agents that cause DNA damage (such as cisplatin or doxorubicin), with microtubule assembly blocking agents (such as taxanes), with topoisomerase inhibitors (such as etoposide), or with anti-metabolic agents (such as 5-fluororacil) (Rosen C J, Adams J S, Bikle D D, Black D M, Demay M B, Manson J E, Murad M H, Kovacs C S. The non-skeletal effects of vitamin D: an endocrine society scientific statement. Endocr Rev. 2012, 33(3):456-92; Deeb K, Trump D L, Johnson C S. Vitamin D signaling pathways in cancer: potential for anticancer therapeutics. Nature Rev Cancer 2007; 7:684-700; Ma Y, Trump D L, Johnson C S. Vitamin D in combination cancer treatment. J Cancer 2010; 1:101-7). However, the main limitation of vitamin D for clinical use is that its administration in pharmaceutical doses induces hypercalcemia (K Deeb, Trump D L, Johnson C S. Vitamin D signaling pathways in cancer: potential for anticancer therapeutics. Nature Rev Cancer 2007; 7:684-700). Therefore, the development of non hypercalcemic vitamin D analogues is particularly important for use in the treatment of diseases in which vitamin D has been shown to be useful in pre-clinical studies. For example, a vitamin D analogue, calcipotriol, is being marketed for the treatment of psoriasis, its administration being topical because of the potential risk of inducing hypercalcemia (Menter A, Korman N J, Elmets C A, Feldman S R, Gelfand J M Gordon K B, Gottlieb A, Koo J Y M, Lebwohl M, Lim H W, Van Voorhees A S, Beutner K R, Bhushan R. Guidelines of care for the management of psoriasis and psoriatic arthritis. J Am Acad Dermatol 2009; 60:643-59).
Thus, the development of new vitamin D analogues with the same properties as the natural hormone, but with little or no ability to induce hypercalcemia, is a goal to be achieved for its use in clinical practice.